HIF-1-alpha and survivin involved in the anti-apoptotic effect of 2ME2 after global ischemia in rats

Abstract

Survivin is an anti-apoptotic gene that decreases the apoptosis by depressing the expression of caspase-3. Hypoxia-inducible factor-1-alpha (HIF-1-alpha) is a transcription factor specifically activated by hypoxia. 2-methoxyestradiol (2ME2) is an estradiol derivative and a known HIF-1-alpha inhibitor. 2ME2 decreased apoptosis by inhibiting HIF-1-alpha. The aim of the present study was to investigate if survivin is involved in the anti-apoptotic effect of 2ME2. Male adult rats were used to make the global ischemia (GI) model. Ten minutes after GI, 2ME2 was injected intraperitoneally (16 mg/kg weight). Rats were killed at 6 hours, 12 hours, 24 hours, 48 hours, 96 hours, and 7 days. GI produced a marked increase in HIF-1-alpha expressions in the hippocampus at 6 hours and peaked at 48-96 hours. The expressions of survivin and caspase-3 were increased lightly in a similar time course. These molecular changes were accompanied by massive cell loss and apoptosis in the hippocampal regions. 2ME2 treatment reduced the expression of HIF-1-alpha, increased survivin expression, and decreased the expression of caspase-3. These results indicate that survivin and HIF-1-alpha were involved in the anti-apoptotic effect of 2ME2 treated following GI. 2ME2 may decrease the HIF-1-alpha expression, up-regulate the survivin expression, inhibit the expression of caspase-3, and finally reduce apoptosis after GI.